Prostaglandin E2Stimulates Insulin-Like Growth Factor I Synthesis in Osteoblast-Enriched Cultures from Fetal Rat Bone*

Abstract

Prostaglandin E2 (PGE2) affects both bone resorption and formation, but its mechanism of action remains unclear. PGE2 is known to elevate intracellular cAMP levels in a variety of culture systems. Agents that increase cAMP in primary osteoblast-enriched (Ob) cultures enhance the synthesis of skeletal insulin-like growth factor I (IGF-I), a potent anabolic factor for bone. A 5 min exposure to PGE2 at 0.01-1 microM enhanced cAMP synthesis in Ob cultures by 8- to 54-fold, and within 6 h produced up to a 3- fold increase in steady state prepro-IGF-I transcripts. The stimulatory effect of PGE2 on IGF-I messenger RNA was first evident within 4 h of treatment and remained elevated for at least 24 h. Furthermore, 0.01-1 microM PGE2 increased immunoreactive IGF-I polypeptide accumulation by 1.9- to 4.7-fold. In contrast PGE2 did not elevate steady state IGF-II mRNA or polypeptide levels within this time frame. Although PTH increase cAMP, intracellular calcium, and PGE2 production by bone cells, our previous studies indicate that the stimulatory effect of PTH on IGF-I production is cAMP, but not calcium dependent. Inhibition of PGE2 synthesis by exposure to indomethacin did not alter basal or PTH-stimulated IGF-I levels, substantiating that the effect of PTH on IGF-I is not PGE2 dependent. These studies indicate that PGE2 production, a feature common to many agents that enhance bone resorption, could contribute to the coupling of bone resorption and new bone formation, by way of its ability to increase cAMP and, consequently, IGF-I synthesis by the osteoblast.